Enantiomerically pure 1,4-benzodiazepine-2,5-diones as Hdm2 antagonists

Bioorg Med Chem Lett. 2006 Jun 15;16(12):3115-20. doi: 10.1016/j.bmcl.2006.03.067. Epub 2006 Apr 21.

Abstract

The 1,4-benzodiazepine-2,5-dione is a suitable template to disrupt the interaction between p53 and Hdm2. The development of an enantioselective synthesis disclosed the stereochemistry of the active enantiomer. An in vitro p53 peptide displacement assay identified active compounds. These activities were confirmed in several cell-based assays including induction of the p53 regulated gene (PIG-3) and caspase activity.

MeSH terms

  • Benzodiazepines / chemical synthesis
  • Benzodiazepines / chemistry*
  • Benzodiazepines / pharmacology*
  • Caspases / metabolism
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydrogen Bonding
  • Models, Molecular
  • Molecular Structure
  • Mutation / genetics
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Enzyme Inhibitors
  • Tumor Suppressor Protein p53
  • Benzodiazepines
  • Proto-Oncogene Proteins c-mdm2
  • Caspases